Transplantation of genetically modified haematopoietic stem cells for Friedreich's Ataxia

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Friedreich's ataxia (FA) is an incurable neurological disorder, typically presenting in late childhood. People with the condition experience progressive accumulation of neurological disability with impaired muscle coordination, weakness, imbalance and difficulties with speech, swallowing, hearing, vision and sensation. It is caused by a genetic mutation in the frataxin gene (FXN), which carries the genetic code for a protein called frataxin, resulting in low levels of frataxin within cells throughout the body causing them to malfunction and eventually die. There have numerous studies looking at possible new therapies for FA, but, as yet, people with FA remain without any treatment to limit disease progression. Our research group have performed bone marrow (BM) stem cell transplantation experiments in mice that have the same genetic mutation as people with FA. When we transplant these FA mice with BM stem cells taken from donor mice with a normal version of the FXN gene, their indicators of disease improve significantly, with improvements in movement, balance, coordination and nerve cell survival. Interestingly, we can track the transplanted BM stem cells and find that large numbers of these cells have travelled into parts of the nervous system affected by FA and helped to protect and repair injured nerve cells. We are currently developing BM stem cell treatments for FA, having recently performed a clinical trial in people with FA looking at how well BM cells can be activated and released into the blood stream with a hope they aid nerve cell repair. The results of this trial are very encouraging; we now want to move our research forward to a definitive treatment for people with FA. Although experimental evidence demonstrates the feasibility of BM stem cell transplantation as an effective therapy for FA, when used clinically, transplanting healthy stem cells from the BM of one person and transferring them to another (called a allogeneic transplant) is associated with hugely significant risks; the challenge of finding an appropriately immune system matched BM donor, the use of powerful drugs to suppress the immune system (resulting in serious complications such as heart disease, neurological injury and infection/sepsis), the risk of severe anaemia and life-threatening complications arising from transplanted cells attacking other cells in the body all remain a possibility. To avoid the major risks of allogeneic BM stem cell transplantation, we propose an alternative approach through removing stem cells from a person with FA and inserting a new FXN gene into the DNA of these cells using genetic engineering techniques. These stem cells, carrying a normal version of the FXN gene, can then be transplanted back into that person to enter the BM, blood and nervous system to then protect and repair to other cells. A vital preliminary stage in the development of this treatment is to fully elucidate the biological mechanisms, safety and efficacy of the approach in an animal model of FA prior to clinical trials. This project will use state-of-the-art technology to insert a new FXN gene into BM stem cells prior to transplanting them into mice containing the same genetic abnormality as people with FA. These mice will be monitored to assess the impact transplantation has on FA disease progression. We will also develop a technique to deliver the FXN to human BM cells to ensure this can be done safely and efficiently in human cells. Following on from this study, we will be in a position to develop new clinical trials in people with FA. Translation of BM stem cell transplantation therapy to clinical practice is realistic; the procedure has been successfully applied in humans for other diseases for over 50 years. We believe that our approach offers a significant advance in therapeutic options for people with this otherwise incurable and untreatable disease.